Four 2-amino-6-halo-2', 3'-dideoxypurine ribofuranosides (ddP), four 6- halo-ddP, two 6-meracapto-ddP, as well as three additional 2',3'-dideoxypurine derivatives were synthesized and evaluated for in vitro activity to suppress the infectivity, replication and cytopathic effect of HIV. 2-Amino-6-fluoro-, 2-amino-6-chloro-, and 6-fluoro-ddPs showed a potent activity against HIV comparable to that of 2',3'-dideoxyinosine (ddI) or 2',3'-dideoxyguanosine (ddG), and completely blocked the infectivity of HIV without affecting the growth of target cells. The comparative order of in vitro anti-HIV activity of the eight 6-haolgen-containing ddPs was 2-amino-5-fluoro, 2-amino-6-chloro, 6-fluoro >2-amino-6-bromo >2-amino-6-iodo, 6-chloro >6-bromo >6-iodo. These compounds also showed a potent activity against HIV-2 and AZT-resistant HIV-1 variants in vitro. Neither the two 6-mercapto-ddPs nor the three 2-.3'-dideoxypurine derivatives were active against HIV-1 in vitro. Several of the 6-halogen-containing ddps were found to have substantial lipophilic character. The lipophilicity order was: 2-amino-6-iodo > 2-amino-6-bromo >2-amino-6-chloro >2-amino-6-fluoro >ddG >ddI with a log P range from +0.5 to -1.2. All eight 6-haologen-containing ddps were substrates for adenosine deaminase (ADA). In the presence of an ADA-inhibitor, 2'-deoxycoformycin, all 6-halogen-containing ddPs failed to exert their in vitro antiretroviral effects. Taken together, these newly synthesized 2-amino-6-halo-ddPs and 6-halo-ddPs compounds may represent a new class of lipophilic prodrugs for ddG and ddI respectively. These HIV infection and, in particular, HIV-caused neurological disorder.